PROJECT SUMMARY RESEARCH PROGRAM The overarching goal of the JAX Cancer Center (JAXCC) Research Program, Genetic Models for Precision Cancer Medicine, is to advance the vision of precision oncology through basic research discoveries with potential for translational and clinical impact. Members use diverse, multi-scale strategies to deconvolute complex cancer systems to their principal components and to investigate the drivers of cancer cell complexity, tumor evolution, and tumor adaptation. Elucidating these fundamental biological processes are key to a principled, mechanistic understanding of the adverse effects of cancer therapy and of treatment resistance. During the current funding period we have expanded, and reshaped, the JAXCC into a new cancer research force with a focus on complex genetics and functional genomics. Research is organized around three complementary Specific Aims. Aim 1 seeks to develop novel organismal, cellular, and computational models of cancer, drawing on the JAXCC's longstanding strengths in model development. Aim 2 examines the genomic instability and genetic complexity of cancer and determines their functional consequences in the cancer cell. Using advanced computational methods and genomic technologies we will interrogate animal models developed in Aim 1 as well as patient samples. Aim 3 investigates how key components of a tumor and the host contribute to cancer biology, examining the cancer cell intrinsic and extrinsic components of a malignant tumor. Results from studies in Aim 3, integrated with the genetic alterations identified in Aim 2 with models developed in Aim 1, will allow us to deconvolute the complex interactions of the tumor and host microenvironments. The 53 full program members of the JAXCC include 33 on the Bar Harbor campus and 20 on the Farmington campus. Through its emphasis on basic research, unique model development, and technological innovation, the program leverages funding from multiple NIH ICs in support of cancer-focused research. More recently, we brought our technologies into the clinical arena through collaborations with SWOG, the Maine Cancer Genomics Initiative, City of Hope, Beth Israel Deaconess Medical Center, University of Connecticut Health Center, and the Connecticut Children's Hospital. The program is supported by $10,401,511 direct costs in NCI and other peer- reviewed cancer-related grants in the last budget year. Over the last grant cycle, CCSG funds have supported 379 publications including 30% intra-programmatic collaborations and 72% with external collaborators. The efforts of the Co-Program Leaders, Drs. Karolina Palucka and Roel Verhaak, and JAXCC leadership have fostered interactivity among JAXCC members through regular Research Program meetings, subsidized travel between campuses, and the JAXCC Annual Retreat. The annual JAXCC Retreat and monthly program meetings are the primary forums that bring together Cancer Center members from both campuses to develop intra- programmatic collaborations and to participate in the planning for resource development and faculty recruitment.